The present invention relates to a convenient process for the preparation of a key intermediate for the synthesis of a dipeptidyl peptidase-IV inhibitor (DP-IV). In particular, the compound named Omarigliptin or (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, having the following structure:
is an active pharmaceutical ingredient which acts as a potent inhibitor of dipeptidyl peptidase-IV, therefore, useful to treat type 2 diabetes, obesity and high blood pressure.
The patent publication WO2010/056708 in the name of Merck & Co., discloses a class of aminotetrahydropyrans, which are potent inhibitors of DP-IV and therefore useful for the treatment of Type 2 diabetes and, in particular, specifically discloses for the first time the compound said above.
The active compound (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine is prepared in example 1 by coupling of the key intermediate 2 named tert-butyl [(2R,3S)-2-(2,5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl]carbamate and having the following structure:
with the Intermediate 5 named 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole and having structure:
followed by the removal of the Boc protecting group.
The preparation of the Intermediate 2 is also disclosed in details in the same patent publication, as a synthetic method involving nine steps of synthesis, starting from 2,5-difluorobenzaldehyde and the final product was purified by column chromatography.
A shorter process for the preparation of the Intermediate 2 is disclosed in US2009/0187028A1 where it is prepared in four steps from the compound named “Ketone 5” or tert-butyl[1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate and having the following structure:

Said “Ketone 5” is prepared in four steps starting from ethyl N -(diphenhylmethylene)glycinate and introducing the aryl group through a Grignard reaction on the compound 2-bromo-1,4-difluorobenzene.
The same procedure disclosed in Lab scale in US2009/0187028A1 is disclosed in industrial scale in WO2013003249 where the preparation of the Intermediate 2 is again carried out through the preparation of the key intermediate (Ketone 5) of formula:

The patent publication WO2013003249 also discloses the preparation of the active ingredient (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine using the same synthons as disclosed in WO2010/056708, as said above, but on multi-kilos scale.
It is therefore clear from the prior art that the compound tert-butyl[1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate and having the following structure:
as well as derivatives thereof are useful intermediates for the preparation of the active pharmaceutical ingredient named (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, i.e. Omarigliptin.
Both the methods disclosed in the prior art for the preparation of tert-butyl[1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate require many synthetic steps, the use of starting materials quite expensive such as 2,5-difluorobenzaldehyde or 2-bromo-1,4-difluorobenzene, the preparation of the Weinreb amide and the use of the Carbonyldiimidazole (CDI).
Moreover, the molar yield of the industrial process disclosed in WO2013003249 for the preparation of the compound tert-butyl[1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate, when carried out in Lab scale, is around 70% and, the step A, is particularly time consuming, which are both factors not optimal for an industrial production of the active ingredient Omarigliptin.